Since proteases including HIV-1 protease bind to their peptide/protein substrates in extended conformations, protease inhibitors constrained to form extended conformations are likely to produce very active protease inhibitors because they are pre-organized to form favorable interactions with the enzyme environment immediately surrounding its active site. This hypothesis will be tested by synthesizing a family of structurally related dipeptide-like molecules that are constrained to adopt the extended conformation. The activity and specificity of these novel protease inhibitors will be compared with currently available HIV-1protease inhibitors. The dipeptide-like molecules will be used as a central core and peripheral groups will be attached to the N- and C- termini that are selected by structural analogy with the most successful currently available HIV-1 protease inhibitors. These hybrid structures will be tested for HIV-1 protease inhibitor activity and specificity to guide optimization of these parameters via an iterative process. Nanomolar HIV-1 protease inhibitors with good specificity are currently used as drugs. But, it is likely that the approach described herein will uncover super-potent lead compounds that inhibit HIV-1 protease at pico-, femto-, or perhaps even sub-femtomolar concentrations. If these inhibitors can also be designed with high specificity and the other issues associated with drug development that are far outside the scope of this small grant can be addressed, then the side effects of long-term treatment will likely be reduced because the dose can be reduced. Furthermore, super-potent drugs could significantly reduce the cost per day of treatment, which is a huge issue for HIV/AIDS treatment in the developing world. [unreadable] [unreadable] [unreadable]